Population-based prospective surveillance of invasive pneumococcal disease was done in Southern California from 31 March 1992 to 1 April 1995; 814 cases were identified, for an incidence of 12.5/100,000 persons/year. The incidence among persons < or = 2, < or = 5, and > or = 65 years of age was 145, 72, and 32/100,000, respectively. More than 95% of cases included bacteremia; incidence of meningitis was 0.8/100,000. Among children < or = 2 years of age, 79% of isolates were obtained in the outpatient setting, compared with 16% of isolates among persons > or = 15 years of age. Eighty percent of isolates were serotypes included in heptavalent pneumococcal conjugate vaccines currently being evaluated. Children < or = 2 years of age were at highest risk of having an isolate resistant to penicillin. Among resistant isolates, high-level resistance increased from 4% to 21% over a 3-year period. Prospective epidemiologic data are needed to perform a protective efficacy trail of pneumococcal conjugate vaccines in infants, among whom most invasive pneumococcal disease is vaccine-preventable.